Follow-up Routines Matter for Adherence to Endocrine Therapy in the Adjuvant Setting of Breast Cancer

Background: Endocrine therapy (ET) adherence leads to increased survival in breast cancer (BC). How follow-up should be done to maximize adherence is not known. Objectives: To assess adherence to ET, factors favouring adherence to ET and effects on survival in a population-based cohort of BC patients in western Sweden. Design: This is a retrospective study. Methods: We included 358 patients operated for oestrogen receptor-positive BC and recommended 5 years of ET, in Region Halland, Sweden, year 2015 to 2016. Demographical, clinical and pathological data and use of ET were retrieved from the electronic medical records. Patients were considered adherent if taking ET for 5 years or during the full extent of the follow-up, until termination of ET due to BC relapse or death and where renewals of prescriptions of ET covered ⩾80% of the ordinated dose. Two follow-up routines were employed, ie, routine A where patients were contacted annually by nurses and a more passive follow-up routine B where patients were only contacted by nurses at 2 years and 5 years following start of ET. Results: Medication persistence for 4 years and more was good and similar between patients initiating aromatase inhibitor (AI) and tamoxifen (75.7% and 72.0%, respectively, P = .43). More patients initiating AIs changed ET due to side effects compared with patients initiating tamoxifen (24.3% vs 9.9%, respectively, P < .0001). Endocrine therapy adherence was better for follow-up routine B than for follow-up routine A (hazard ratio [HR] = 2.71 [1.44-5.09], P = .0027). Conclusions: Adherence to ET in BC is high in Western Sweden. Less regular nurse-initiated contacts between BC patients and nursesled surprisingly to a better adherence than a more regular nurse-initiated contact.


Introduction
2][3][4] Adjuvant treatment after surgery with 5 year endocrine therapy (ET) in the form of tamoxifen or aromatase inhibitors (AIs) contributes significantly to increased survival in ER-positive BC. 5,6 Endocrine therapy is, however, associated with side effects such as hot flushes, night sweats, oedema and vaginal dryness, which may lead to poor compliance and early discontinuation. 7][10] Poor compliance may consequently 2 Breast Cancer: Basic and Clinical Research lead to increased BC recurrence and worse overall survival (OS). 11,124][15] There is therefore an essential need to identify follow-up routines to support BC women on ET and to enable compliance to ET and prevent discontinuation.How follow-up should be conducted to optimize compliance is at present not known.Studies show that regular contact with a nurse leads to better compliance to ET in BC patients. 16,17Trials are also ongoing to assess the efficacy of telephone-based training programmes to cope with side effects of ET, text message reminders and telephone-based counselling to improve adherence to ET in BC patients. 18,19urgery and adjuvant therapy against BC are given at Varberg Hospital and Halmstad Hospital in Region Halland in western Sweden.The centres have employed different follow-up routines for patients on ET due to BC, ie, the contact with nurses has either been more regular and more initiated by nurses or less regular and more initiated by the patients.Here, we assessed whether adherence to ET in BC patients is affected by the degree of nurse-driven contact with the patients.Moreover, we assessed which factors that correlate with adherence to ET and how changes of ET occur over time in the adjuvant setting of BC.

Methods
All patients undergoing surgery for breast lumps in 2015 to 2016 in Region Halland, Sweden, were identified in the electronic medical records.The cohort consisted of 743 patients where 385 patients were excluded from the study as they did not meet inclusion criteria (Figure 1).The study cohort consisted of 358 patients who met inclusion criteria, ie, they were diagnosed and operated for ER+ (⩾10%)-positive BC and were recommended adjuvant ET at a multidisciplinary conference board where surgeons, oncologists, pathologists and radiologists attended.All patients were informed about their tumour type and lymph node status.Moreover, all patients included were traceable during the follow-up time, ie, staying in the region during the follow-up time.Demographical data, clinical data and pathological data were retrieved from the electronic medical records and registered in a database.The initial recommended ET, any change of ET either due to side effects, the patient's own choice or due to predetermined switch to other ET, causes of change of ET, side effects of ET and points in time for change of ET were registered in the database.Moreover, the frequency of renewals of prescriptions of ET was recorded.Any relapse of BC and death during the follow-up time were registered in the database.Cut-off date was set on December 17, 2020.
All patients were prescribed at least 5 years of ET.The patient was considered adherent to the initial ET plan if the patient took ET during 5 years or during the full extent of the follow-up time, until termination of ET due to BC relapse or death and if renewals of prescriptions of ET covered at least 80% of the ordinated dose during the follow-up time.Patients were also considered non-adherent if they decided to stop ET after discussion with the oncologist or surgeon.Patients were followed until day of pre-termination of ET or when day of non-adherence occurred, death, BC relapse or cut-off date.Information on cause of death was retrieved from the medical chart of the patient.Whether the cause of death was BC, other cause or if information on cause of death was missing was also retrieved from the medical chart.Follow-up routines differed between Varberg Hospital and Halmstad Hospital due to different follow-up routines developed over time at the two hospitals.At both hospitals the patient had a follow-up meeting with a surgeon or an oncologist at 1 year, a phone call from a nurse at 2 years and a concluding phone call from a nurse at 5 years following start of ET.At Halmstad Hospital, a follow-up phone call from a nurse was made 3 months following initiation of ET.At Varberg Hospital, a more active nurse-driven follow-up routine (follow-up A) was employed in patients diagnosed in 2015 and before, ie, a phone call from a nurse was made here also at 3 years and at 4 years after initiation of ET (see Figure 1).Patients were informed to contact the clinic for renewal of prescription of ET, if intolerable side effects to ET appeared and/or wanting to make any change in ordinated ET.In the analysis, follow-up routines were subdivided into a more active nurse-driven follow-up routine A (119 patients, 33.7%) employed at Varberg Hospital in 2015 and a more patient-driven follow-up routine B (234 patients, 60.3%) employed at Halmstad Hospital and at Varberg Hospital in 2016 (see Figure 1).As noted in Figure 1, patients who became 75 years old during follow-up time or older were followed according to routine A in Varberg, regardless of which year the patient had BC surgery.

Statistics
No power analysis was performed since we included all patients operated for BC during 2015 to 2016 in Region Halland.The χ 2 -test was used to compare categorical variables between groups.The Mann-Whitney test was used to compare continuous variables.Bivariate logistic regression analysis was performed and crude odds ratios and adjusted odds ratios were calculated for explanatory variables correlating with the dichotomous dependent variable adherence (adherent vs non-adherent).Adherence to ET over time was depicted with the Kaplan-Meier analysis and adherence between groups was compared using a 2-sided log-rank test (Mantel-Cox).Cases where termination of ET was due to progressive disease or death were censored.Statistical significance was set at P values less than .05.Mean value ± standard error of the mean (SEM) is given in the text or median (95% confidence interval) where indicated.IBM SPSS Statistics version 26 (IBM Corp, Armonk, NY, USA) and GraphPad Prism program 9.1.0(GraphPad Software, Inc, San Diego, CA, USA) were used to analyse data.

Description of the cohort
Demographical, clinical and pathological data are displayed in Table 1.Median age in the cohort was 65.5 years.In the cohort, 6.8% of patients were previously diagnosed with ipsilateral breast.Patients with bilateral and multifocal BC constituted 1.7% and 9.9% of the cohort, respectively.Non-special type carcinoma (NST) and lobular carcinoma constituted 76.5% and 15.9%, respectively, of the breast tumours.T1 tumours were most common (58.1%) and 27.9% of the cohort had lymph node metastases.Breast tumours were positive for HER2 in 11.9% of cases and trastuzumab was given to 76.2% of patients with HER2-positive BC.Adjuvant radiotherapy and chemotherapy were given to 72.2% and 32.3% of the cohort, respectively.During follow-up, 9.1% of patients had recurrence (local + distant) and 1.1% of the cohort were diagnosed with a contralateral BC.During follow-up, 8.8% died and 2.5% died of BC.

Adherence to endocrine therapy
Among patients offered ET, 43.3% were prescribed tamoxifen and 56.7% AIs (letrozole, anastrozole, exemestane).Five patients were ordinated ET but did not initiate ET (1.3%).Median time from start of ET to end of follow-up was 4.66 (4.44-4.91)years and 4.49 (4.35-4.61)years for follow-up A and follow-up B, respectively (P = .90).Planned switch from AI to tamoxifen was more common than from tamoxifen to AI, ie, 34.7% (70/202) and 4.0% (6/151) of cases, respectively (P < .0001).Among patients initiating AI, 24.8% changed to tamoxifen or other AI due to side effects, whereas 9.9% of patients initiating tamoxifen changed to AI or fulvestrant due to side effects (P = .0004;Figure 2).
In average, patients prescribed tamoxifen had their first change of ET after 57 ± 13 weeks compared with after 61 ± 7 weeks in patients prescribed AI (P = .82).No difference in median time on ET was observed in patients who initiated treatment with AI compared with patients initiating treatment with tamoxifen (55.2 [53.1-56.8]vs 53.7 [51.6-55.3]months, respectively, P = .07).Adherence of tamoxifen and AI was similar (hazard ratio [HR] = 1.17 [0.64-2.13];P = .71;Figure 3A) and medication persistence for 4 years and more was 72.0% for patients initiating tamoxifen and 75.7% for patients initiating AI (P = .43;Table 2).Adherence to ET was better for the follow-up routine B than for the follow-up routine A (HR = 2.71 [1.44-5.09],P = .0027;Figure 3B and Table 2) and follow-up routine A constituted an independent factor associated with worse adherence (adjusted odds ratio [AOR]: 4.48 [1.33-15.02],P = .02;Table 3).Experiencing ET side effects was also an independent factor correlating with worse adherence to ET (AOR = 3.13 [1.30-7.50]).
Being on systemic hormone replacement therapy (HRT) tended to be negatively associated with adherence in univariate regression analysis but was not significant in multivariate analysis (Table 3).Adherence to ET did not depend on characteristics of the tumour such as tumour type, size, grade, HER2 status, nor lymph node status or adjuvant treatments including radiotherapy, chemotherapy and trastuzumab therapy.Neither was age or first choice of ET predictive to adherence (Table 3).The most common reported causes related to interruption of ET were arthralgia/myalgia (23.7%), sweating/hot flushes (21.1%), depression (18.4%) and tiredness/lack of energy (18.4%;Table 4).Patients under follow-up routine A and B constituted 33.7% (119) and 66.3% (234) of the cohort, respectively.Among non-adherent patients under follow-up routine A, 52.2% of the non-adherent patients had a discussion with their physician and a mutual understanding in the decision to stop ET, whereas 47.8% stopped treatment without the recommendation or knowledge of their physician.The corresponding figures in patients under follow-up routine B were 35.0% and 65.0%, respectively (P = .26between followup routines A and B).For patients where physicians were involved in the decision to stop ET compared with other patients, attendance at Varberg Hospital was more common (78.9% vs 49.4%, respectively, P = .01),follow-up routine A was more common (63.2% vs 32.0%, respectively, P = .007),patients had more often a previous cancer (21.1% vs 6.0%, respectively, P = .03),more patients tended to be prescribed    tamoxifen as first ET (68.4% vs 41.0%, respectively, P = .06)and more patients changed their ET (P = .03,Table 5).In patients under follow-up routine A, 18.5% stopped ET due to side effects and 14.5% due to progression or death.The corresponding figures in patients under follow-up routine B were 6.8% and 6.8%, respectively (P < .0001 between followup routines A and B).

Discussion
In this study, we wanted to explore the natural history of adherence to ET.We show that adherence to ET in BC patients is high in Halland Region.Our study indicates that patients with less nurse-initiated contact may have better adherence to ET compared with patients with more nurse-initiated contact.No differences were observed in adherence and in survival between patients initiating tamoxifen and AI in the adjuvant setting.However, change of ET from AI to tamoxifen was more common than from tamoxifen to AI.Previous HRT tended to be associated with non-adherence to ET as shown in previous studies. 9,20This can be explained by that women on HRT tend to develop intolerable symptoms due low oestrogen.More information and support during ET are needed to elevate compliance in this group.All patients in our studied cohort were given information orally and in written form of the pathological and clinical data of the tumour.In contrast to previous studies, 9 characteristics of the tumour such as tumour size, grade and lymph node metastasis as well as adjuvant treatment were not associated with adherence.Our study may, however, have been underpowered to assess these correlations.][23][24] The number of women in our cohort younger than 40 years constituted only 1.7%, and therefore, adherence in this age group was difficult to assess.Exposure to adjuvant chemotherapy has in some studies been identified as a negative predictor of adherence in early BC in women younger than 40 years of age. 25Other studies have instead shown that it is a positive predictor of adherence. 9[24]  Footnote.For changed endocrine therapy 'clinical causes' include recurrence, oophorectomy and potentiation of therapy.Binary logistic regression analysis was performed on factors correlating with non-adherence.AOR = adjusted odds ratio; CI = confidence interval; HRT = hormone replacement therapy.a Tamoxifen + salpingo-oophorectomy.

Table 3. (Continued)
Patients on AI experienced more side effects than patients on tamoxifen.Experiencing side effects of ET was also an independent factor correlating with worse adherence.It was more common to change from AI to tamoxifen than the opposite direction.As earlier studies have shown, 20 changing ET due to side effects was correlated with poorer adherence.This appears logical as patients normally are prescribed another type of ET if intolerable side effects appear before interrupting treatment.However, whether patients started ET with tamoxifen or AI did not seem to be associated with adherence to ET.
We report a relatively high persistence to ET in the adjuvant setting of BC where medication persistence for 4 years and more was 75.7% for patients initiating AI and 72.0% for patients initiating tamoxifen.To note, compliance figures vary between studies, ie, compliance in the adjuvant setting of BC has been reported to be 69% in Regions Stockholm-Gotland and Region Uppsala-Örebro, whereas compliance was 92% in Region Jönköping in Sweden. 26,27Variations of compliance may not only be due to any differences in patient cohorts but also how compliance is defined.Moreover, treatment traditions at different clinics may also contribute to compliance.
Earlier studies suggest that high availability and information about benefits of ET and potential side effects are of importance to compliance, 28 but exactly how follow-up should be arranged to result in best compliance is not known.Breast cancer patients adherent to ET are more likely to contact their nurse when they experience side effects to ET. 16 This implies that availability of health care staff is important to improve adherence.In our study, all patients, regardless of follow-up routine, were given contact details to a specialized nurse and were informed to call in case of side effects or if they had any questions about their ET.This available support and consult may have contributed to the high adherence observed in the cohort.To our surprise, a more active monitoring, where the nurse contacted the patient annually, more often led to a poorer adherence to ET compared with a more patient-controlled follow-up.However, the percentage in decisions where physicians were involved in ending ET and the percentage in decisions where patients decided independently to end ET were the same in patients under follow-up routines A and B. Therefore, we cannot conclude that lower adherence in patients under follow-up routine A solely depended on physicians and nurses driving patients to end ET.The contact may, however, have triggered the patient independently to end ET.When contacted by their nurse, patients had the opportunity to discuss their ET and any side effects, where quality of life was weighted against potential benefits of continued ET based on patient and tumour factors.
The strength of our study is that we were able to track almost all patients during follow-up and analysed how changes in ET occur over time.The follow-up time varied depending on date of surgery and if the patient underwent chemotherapy before starting ET.Most patients in routine A were included in 2015 (69.7%), whereas most patients in routine B (60.7%) were included in 2016.This means that participants included in 2016 had less time to become non-adherent than participants included in 2015.However, there was no difference in followup time between the 2 assessed follow-up routines where patients from 2015 and 2016 were combined.A limitation of the study is that the sample size was fixed to all patients treated for breast lump in our region between 2015 and 2016, and no power analysis was therefore performed.To assess adherence, we analysed whether patients had asked for new prescriptions of ET, however, we did not record whether the prescribed ET was collected from the pharmacy, and this is a bias in our study.Breast cancer-specific survival could also have been over-estimated in our study as cases were retrieved only from the medical records of the patients.However, as migration was low in our cohort, we are convinced that our estimate of survival was close to accurate.The study was conducted in two hospitals and a small number of physicians were involved in treatment decisions.Therefore, we cannot rule out that treatment traditions in physicians and nurses working at the two clinics may have affected the observed adherence differences between follow-up routines A and B. To note, how tamoxifen vs AI was used and the involvement of physicians in the decision to stop ET were different between the two hospitals assessed.Compliance differences in the regions of Sweden have also been observed in previous studies. 9

Figure 1 .
Figure 1.Flow chart of breast cancer patient treatments, adherence to endocrine therapy and follow-up routines.

Figure 2 .
Figure 2. Flow chart of changes and termination of ET in breast cancer patients.

Figure 3 .
Figure 3. Adherence to endocrine therapy depending on first choice of endocrine therapy (A) and follow-up (B).

Table 1 .
Characteristics of patients, surgical and oncological treatments and tumour characteristics.

Table 2 .
Number of years on endocrine therapy.

Table 3 .
Bivariate logistic regression analysis on explanatory variables correlating with adherence to endocrine therapy.

Table 4 .
Side effects of 38 patients terminating in advance endocrine therapy.

Table 5 .
Factors correlating with recommendation by physician to stop endocrine therapy.Footnote.P values were determined with the 2-sided χ 2 -test or the Fisher exact test.a Not included are patients not lymph node operated or where sentinel node was not found.